MicroRNA-22 downregulation by atorvastatin in a mouse model of cardiac hypertrophy: a new mechanism for antihypertrophic intervention.

Growing evidence shows that microRNAs (miRNAs) are involved in various cardiac processes including cardiac hypertrophy. However, the modulation of miRNA by pharmacological intervention in cardiomyocyte hypertrophy has not been disclosed yet. methods: We constructed neonatal rat cardiomyocyte hypertrophy induced by angiotensin II stimulation and subjected to cardiomyocyte immunochemistry, qRT-PCR and immunoblotting analysis. In addition, we constructed the mouse cardiac hypertrophy using angomir-22 stimulation and demonstrated the potential antihypertrophic mechnism of atorvastatin. The results showed that a collection of miRNAs were aberrantly expressed in hypertrophic cardiomyocytes induced by angiotensin II stimulation. In addition, overexpression of miR-22 was found in angiotensin II-induced hypertrophic cardiomyocytes, whereas administration of atorvastatin could reverse the upregulation of miRNA-22 nearly back to the control level. Furthermore, up-regulation of miRNA-22 in cardiomyocytes in vitro and in vivo could induce cardiac hypertrophy, which could suppress the protein level of phosphatase and tensin homolog deleted on chromosome ten (PTEN). Concomitantly, the production of ANP, BNP and β-MHC was enhanced and cardiomyocyte size was increased. However, atorvastatin could markedly knockdown miRNA-22 expression and reverse these changes in cardiomyocytes. These results suggest that the contribution of atrovastatin to cardiomyocyte hypertrophy may be involved in downregulation of miRNA-22 expression, which modulates the activity of PTEN in cardiomyocyte hypertrophy. conclusion: This study demonstrates for the first time the modulation of miRNA-22 can be achieved by pharmacological intervention. The data generated from this study provides a rationale for the development of miRNA-based strategies for antihypertrophic treatment.

Tu Y ，Wan L ，Bu L ，Zhao D ，Dong D ，Huang T ，Cheng Z ，Shen B ... -  《-》

Qiliqiangxin Attenuates Phenylephrine-Induced Cardiac Hypertrophy through Downregulation of MiR-199a-5p.

Qiliqiangxin (QL), a traditional Chinese medicine, has long been used to treat chronic heart failure. Previous studies demonstrated that QL could prevent cardiac remodeling and hypertrophy in response to hypertensive or ischemic stress. However, little is known about whether QL could modulate cardiac hypertrophy in vitro, and (if so) whether it is through modulation of specific hypertrophy-related microRNA. The primary neonatal rat ventricular cardiomyocytes were isolated, cultured, and treated with phenylephrine (PE, 50 µmol/L, 48 h) to induce hypertrophy in vitro, in the presence or absence of pretreatment with QL (0.5 µg/ml, 48 h). The cell surface area was determined by immunofluorescent staining for α-actinin. The mRNA levels of hypertrophic markers including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain (MYH7) were assayed by qRT-PCRs. The protein synthesis of cardiomyocytes was determined by the protein/DNA ratio. The miR-199a-5p expression level was quantified in PE-treated cardiomyocytes and heart samples from acute myocardial infarction (AMI) mouse model. MiR-199a-5p overexpression was used to determine its role in the anti-hypertrophic effect of QL on cardiomyocytes. PE induced obvious enlargement of cell surface in cardiomyocytes, paralleling with increased ANP, BNP, and MYH7 mRNA levels and elevated protein/DNA ratio. All these changes were reversed by the treatment with QL. Meanwhile, miR-199a-5p was increased in AMI mouse heart tissues. Of note, the increase of miR-199a-5p in PE-treated cardiomyocytes was reversed by the treatment with QL. Moreover, overexpression of miR-199a-5p abolished the anti-hypertrophic effect of QL on cardiomyocytes. QL prevents PE-induced cardiac hypertrophy. MiR-199a-5p is increased in cardiac hypertrophy, while reduced by treatment with QL. miR-199a-5p suppression is essential for the anti-hypertrophic effect of QL on cardiomyocytes.

Zhang H ，Li S ，Zhou Q ，Sun Q ，Shen S ，Zhou Y ，Bei Y ，Li X ... -  《-》

Myocyte-specific enhancer factor 2C: a novel target gene of miR-214-3p in suppressing angiotensin II-induced cardiomyocyte hypertrophy.

Tang CM ，Liu FZ ，Zhu JN ，Fu YH ，Lin QX ，Deng CY ，Hu ZQ ，Yang H ，Zheng XL ，Cheng JD ，Wu SL ，Shan ZX ... -  《Scientific Reports》

GDF11 Attenuated ANG II-Induced Hypertrophic Cardiomyopathy and Expression of ANP, BNP and Beta-MHC Through Down- Regulating CCL11 in Mice.

Growth differentiation factor 11 (GDF11) decreases with age, and increased C-C motif chemokine 11 (CCL11) is involved in aging. However, the effects of GDF11 on Angiotensin II (ANG II)-induced hypertrophic cardiomyopathy and expression of markers for volume overload and hypertrophy such as ANP, BNP and beta-MHC, as well as the relationship between GDF11 and CCL11 in hypertrophic cardiomyopathy are unclear. Therefore, the current study aimed to examine the effects of GDF11 on ANG II-induced hypertrophic cardiomyopathy and expression of ANP, BNP and beta-MHC in mice, and explore possible molecular mechanisms. Vectors were constructed and viruses were packaged. Mouse cardiomyocytes were treated with ANG II for 24 h. Meanwhile, mouse cardiomyocytes were divided into 4 groups: (1) control; (2) ANG II; (3) ANG II+GDF11; and (4) ANG II+CCL11. Furthermore, mouse cardiomyocytes were treated with GDF11 and CCL11 proteins for 48 h, respectively. The thickness of IVS and LVPS during systole and diastole were measured by cardiac ultrasound in the mouse model of hypertrophic cardiomyopathy. The relative expression of ANP, BNP, beta-MHC, CCL11 and GDF11 in cardiomyocytes or heart tissue of mice was detected by qPCR or Western blot. 3'- UTR luciferase reporter assay was utilized to examine the relationship between GDF11 and the expression of CCL11. The expression of ANP, BNP, and beta-MHC in mouse cardiomyocytes was significantly increased after the cells were treated with 800 nM ANG II, which was utilized in the following cell experiments. After ANG II treatment, 0.2 ng/ml GDF11 group displayed the highest inhibition of expression of ANP, BNP and beta-MHC in mouse cardiomyocytes, whereas 50 ng/ml CCL11 group displayed the highest stimulation of the expression. GDF11 at 10 ng/ml significantly decreased the expression of CCL11 in mouse cardiomyocytes as compared to the control group. Mice treated with ANG II had increased thickness of IVS and LVPS during both systole and diastole, which was significantly attenuated by GDF11 overexpression. GDF11 overexpression attenuated the increase in expression of ANP, BNP and beta-MHC in the mice model of hypertrophic cardiomyopathy. The relative serum concentration of GDF11 was markedly decreased, and CCL11 was dramatically increased in mice with hypertrophic cardiomyopathy. GDF11 overexpression restored the serum concentration of GDF11 and CCL11 in the mice model of hypertrophic cardiomyopathy. In addition, GDF11 interference group had markedly increased expression of CCL11, whereas GDF11 overexpression group had significantly decreased expression of CCL11 in luciferase reporter assay. GDF11 attenuated ANG II-induced hypertrophic cardiomyopathy and expression of ANP, BNP and beta-MHC through down-regulating CCL11 in mice.

Zhang C ，Wang Y ，Ge Z ，Lin J ，Liu J ，Yuan X ，Lin Z ... -  《-》

Let-7a Is an Antihypertrophic Regulator in the Heart via Targeting Calmodulin.

Zhou X ，Sun F ，Luo S ，Zhao W ，Yang T ，Zhang G ，Gao M ，Lu R ，Shu Y ，Mu W ，Zhuang Y ，Ding F ，Xu C ，Lu Y ... -  《International Journal of Biological Sciences》